MECHANISMS OF RADIORESISTANCE IN TERMINALLY DIFFERENTIATED CELLS
OF MATURE RETINA
V.A. Tronov,1,2,* Yu.V. Vinogradova,2 M.Yu. Loginova,3 V.A. Paplinskaya,4 M.A. Ostrovsky 2
1 N. N. Semenov Institute of Chemical Physics RAS, Moscow,
2Joint Institutes of Nuclear Problems, Dubna, 3 N.M. Emanuel Institute of Biochemical Physics RAS
and 4 N.K. Koltsov Institute of Biology of Development RAS, Moscow;
* e-mail: vtronov@yandex.ru
Retinopathy of animals is induced by many agents damaging DNA. This fact shows that DNA lesions may
initiate retinal degeneration. The aim of our work was to study the effects of gamma and proton irradiation, and
methylnitrosourea (MNU) on mice retina. We evaluated morphological changes, DNA damage and repair in retina,
and expression of 5 proteins participating in apoptosis: p53, ATM, FasR, PARP and caspase 3 active. Dose
of 14 Gy is equitoxic in terms of induction of DNA single strand breaks by both gamma and proton irradiation.
But protons were 2 fold more effective than gamma-rays in induction of DNA double strand breaks. All breaks
were repaired within ≤ 10 h. Irradiation resulted in increased expression of p53 and ATM. But no sings of cell
death and retinal degeneration were observed during 7 days after irradiation. Proton irradiation in dose of 25 Gy
resulted in increasing over time destructive changes localized mainly in photoreceptor layer of retina. These
changes were followed by increased expression of proapoptotic proteins. A single systemic administration of
MNU (70 mg/kg) increased intracellular levels of p53, PARP, FasR, caspase 3 active, which was followed by
destructive changes in retina with sings of apoptosis of photoreceptors. As in the case of irradiation, the 2-fold
dose reduction of MNU abrogated cytotoxic effect of MNU on retina. High level of spontaneous DNA damage
such as apurine and apyrimidine sites were observed in mouse retina. The results of our study demonstrate the
occurrence of genotoxic threshold in the initiation of retinal cell death in vivo. Topoisomerase 2 of retina is suggested
to translate primary DNA damage to cytotoxic effect.
Key words: retina, postmitotic cells, ionizing radiation, methylnitrosourea, DNA damage, genotoxic
threshold, topoisomerase 2
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